The pathobiochemical bases controlling bone formation in physiologic situations and disease states are not known. This is a biochemical question of critical importance since osteoporosis, a low bone mass disease characterized by a relative decrease of bone formation, is the most prevalent disease in developed countries. Dr. Karsenty and his lab have recently demonstrated that leptin is a powerful inhibitor of bone formation whose absence leads to a high bone mass phenotype even in ovariectomized animals and those with increased circulating glucocorticosteroids. This latter result indicates that leptin may be the most powerful regulator of bone formation identified to date, as it is the only regulatory pathway that can overcome the deleterious consequences of hypogonadism and hypercorticosteroidism on bone mass. Lastly, Dr. Karsenty has shown that leptin must bind to its hypothalamic receptor, not to the osteoblast, to exert its regulatory role on bone formation, thus uncovering that bone formation is a central function. Dr. Karsenty and his lab intend in this application to explore the molecular bases of leptin action on bone formation. They believe that this project may lead to the design of novel therapeutics enhancing bone formation for osteoporosis. The specific aims of this application are: 1. To compare the potency of leptin in controlling bone mass and body weight and the relative efficiency of peripheral versus central delivery of leptin in the control of bone formation. 2. To determine whether a naturally occurring soluble (decoy) form of the leptin receptor can prevent leptin inhibitory action on bone formation. 3. To determine whether or not leptin affects bone formation by acting on early osteoblast progenitors. 4. To determine whether leptin uses a pituitary or a neuronal pathway to regulate bone formation. 5. To identify the hypothalamic nuclei that are involved in the regulation of bone formation by leptin.